Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Nephrology and Renal Transplantation, University Hospitals Leuven and Nephrology & Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
PLoS Med. 2020 Jun 15;17(6):e1003140. doi: 10.1371/journal.pmed.1003140. eCollection 2020 Jun.
Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs.
We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 (ClinicalTrials.gov Identifier NCT02811835). Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7-9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk (hazard ratio [HR] 1.86, 95% CI 1.38-2.52, P < 0.001) compared with no use. After adjustment for potential confounders, PPI use remained independently associated with mortality (HR 1.68, 95% CI 1.21-2.33, P = 0.002). Moreover, the HR for mortality risk in KTRs taking a high PPI dose (>20 mg omeprazole equivalents/day) compared with patients taking no PPIs (HR 2.14, 95% CI 1.48-3.09, P < 0.001) was higher than in KTRs taking a low PPI dose (HR 1.72, 95% CI 1.23-2.39, P = 0.001). These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation.
We demonstrated that PPI use is associated with an increased mortality risk in KTRs, independent of potential confounders. Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages. Because of the observational nature of our data, our results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs.
ClinicalTrials.gov Identifier: NCT02811835, NCT01331668.
质子泵抑制剂（PPIs）在肾移植受者（KTRs）中被广泛用于慢性治疗。然而，人们对 PPI 治疗的潜在长期并发症表示担忧。本研究旨在探讨 PPI 使用与 KTR 超额死亡风险之间的关系。
我们使用单中心前瞻性队列 703 例稳定的门诊 KTR 患者（2008 年 11 月至 2011 年 3 月期间在格罗宁根大学医学中心就诊）的多变量 Cox 比例风险回归分析来研究 PPI 使用与死亡率风险之间的关系（ClinicalTrials.gov 标识符：NCT02811835）。在来自鲁汶大学医院的 656 例前瞻性 KTR 队列中进行了结果的独立复制（NCT01331668）。平均年龄为 53±13 岁，57%为男性，56.6%使用了 PPI。在中位数为 8.2（4.7-9.0）年的随访期间，有 194 例 KTR 死亡。在单变量 Cox 回归分析中，与未使用者相比，PPI 使用与近两倍的死亡率风险相关（风险比[HR] 1.86，95%CI 1.38-2.52，P<0.001）。在调整了潜在混杂因素后，PPI 使用与死亡率仍呈独立相关（HR 1.68，95%CI 1.21-2.33，P=0.002）。此外，与未使用 PPI 的患者相比，使用高剂量 PPI（>20mg 奥美拉唑等效剂量/天）的 KTR 患者的死亡率风险 HR（HR 2.14，95%CI 1.48-3.09，P<0.001）高于使用低剂量 PPI 的患者（HR 1.72，95%CI 1.23-2.39，P=0.001）。这些发现在鲁汶肾移植队列中得到了复制。本研究的主要局限性在于其观察性设计，这使得无法得出因果关系的结论。
我们证明了 PPI 使用与 KTR 的死亡率风险增加相关，这与潜在的混杂因素无关。此外，我们的数据表明，这种风险在使用高剂量 PPI 的 KTR 中最高。由于我们的数据是观察性的，因此需要进一步证实，然后才能建议避免 KTR 长期使用 PPI。
ClinicalTrials.gov 标识符：NCT02811835，NCT01331668。
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